Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([OH:20])[CH:8]=[C:7]([O:9]C)[N:6]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[NH:4]1.B(Cl)(Cl)Cl.O.C(Cl)Cl>ClCCCl>[OH:9][C:7]1[N:6]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[NH:4][C:3]([O:2][CH3:1])([OH:20])[CH:8]=1
Reactant: COC1=CC(O)(OC)NC(c2nc(C(F)(F)F)cs2)=N1
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: COC1(O)C=C(O)N=C(c2nc(C(F)(F)F)cs2)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of compound 288 (460 mg, 1 eq.) in DCE (10 mL) was added BCl3 (3.16 mL, 2 eq.). The mixture was stirred at 60° C. for 16 hrs. Water and DCM were then added. Organics were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated in a DCM/pentane mixture to yield compound 289 as a beige solid in 38% yield. MS (ESI, EI+): m/z=278 (MH+).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[N:17]([C:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[S:4][N:3]=2)[N:16]=1
Reactant: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Reactant: Cc1cc(C)[nH]n1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)n(-c2nsc3ccc([N+](=O)[O-])cc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
A mixture of 3-chloro-5-nitrobenzisothiazole (5.3 g, mmol), 3,5-dimethylpyrazole (2.40 g, 25.0 mmol) and pyridine is stirred overnight at reflux, cooled to room temperature and diluted with ethyl acetate. The resultant mixture is filtered and the filtrate is washed with three portions of 10% hydrochloric acid and one portion of water. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound (2.85 g, 43.8%) which is identified by NMR spectral analysis.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][O:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccoc1
Product: c1cc(-c2c3c(nn2C2CCCC2)CCNCC3)co1
Yield: 83.6 %

Procedure:
The title compound (101 mg) was prepared according to Example 180 using 202 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 149 mg of 3-furanboronic acid. MS (ESI): exact mass calculated for C16H21N3O, 271.17; found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.73-7.72 (m, 2H), 6.57-6.56 (m, 1H), 4.64 (m, 1H), 3.40-3.38 (m, 2H), 3.16-3.14 (m, 2H), 2.86-2.84 (m, 2H), 2.03-1.91 (m, 6H), 1.66-1.64 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](Br)[CH:18]=3)([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:24]#[N:25])([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cccc(Br)c2)C2CCC1CN(Cc1ccccc1)C2
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(C2(O)C3CCC2CN(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Benzyl-8-(3-bromo-phenyl)-3-aza-bicyclo[3.2.1]octan-8-ol (2.17 g, 5.83 mmol) and zinc cyanide (1.03 g, 8.75 mmol) were combined in DMF (30 mL), degassed (evac/N2 purge 3×) then charged with tetrakistriphenylphosphine palladium (0) (3.37 g, 2.91 mmol). The resulting reaction mixture was heated to 85 □ C. in an oil bath for 5 h (or until complete by TLC). After cooling to room temperature, the reaction mixture was filtered through a Celite pad and rinsed with EtOAc. The filtrate was extracted with 1 N HCl (2×50 mL) then neutralized to pH 8 with 1 N NaOH and saturated aqueous NaHCO3 solution, causing an emulsion to form. The product was extracted with EtOAc (3×100 mL), washed with saturated aqueous NaCl solution (2×100 mL), dried over Na2SO4, filtered and concentrated. The resulting crude product was dissolved in ether (100 mL), washed with 50% saturated aqueous NaCl solution (4×100 mL), dried over Na2SO4, filtered and concentrated to a brown oil (1.86 g, 100%). (TLC 40% EtOAc/Hexanes Rf 0.42); 1H NMR (400 MHz, CDCl3) δ 7.76–7.72 (m, 2H), 7.55 (br d, J=7.9 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.36–7.20 (m, 5H), 3.59 (br s, 2H), 2.84 (d, J=10.8 Hz, 2H), 2.61 (br d, J=10.8 Hz, 2H), 2.36 (br, s, 2H), 1.83 (d, J=7.5 Hz, 2H), 1.35 (m, 2H); APCI MS m/z 319.2 (M+1)+.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH:17]O>C(#N)C.[Pd]>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5]([CH3:6])=[O:17]
Reactant: OO
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Pd]
Solvent: CC#N
Product: CS(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 200 ml of acetonitrile is dissolved 37 g of BOC-(D)-Met-OH, followed by adding 19 ml of a 30% aqueous solution of hydrogen peroxide, and the mixture is stirred for 8 hours at room temperature. Palladium black is added to the reaction mixture, and then the mixture is stirred for one hour. Palladium black is filtered off, and then acetonitrile is distilled off. The residue is extracted with 300 ml of n-butanol. The n-butanol layer is washed with aqueous solution of NaCl, and then n-butanol is distilled off. The residue is recrystallized from diethyl ether and, then,AcOEt-diethyl ether to give 32 g of crystals, m.p. 125°-126° C., [α]D23 +7.2° (C=0.5, DMF), Rf1 =0.27.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C.CO>ClCCl>[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)=[O:10])=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(NC(C)=O)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 514.0 mg (1.26 mmol) of N-(4-aminophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 221 in 10 ml of dichloromethane were added 0.18 ml (1.89 mmol) of acetic anhydride and 0.53 ml (3.78 mmol) of triethylamine under ice-cooling. After the resulting mixture was stirred overnight at room temperature, 0.18 ml (1.89 mmol) of acetic anhydride and 0.53 ml (3.78 mmol) of triethylamine were added thereto, followed by overnight stirring. To the reaction mixture was added methanol and the solvent was evaporated. Then, the residue was purified by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.N#N.[Br:17][C:18]1[CH:30]=[CH:29][C:28]2[C:27]3[C:22](=[CH:23][C:24]([Br:31])=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH:19]=1.I[C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.[Cu]Cl.O>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:21]2[C:22]3[CH:23]=[C:24]([Br:31])[CH:25]=[CH:26][C:27]=3[C:28]3[C:20]2=[CH:19][C:18]([Br:17])=[CH:30][CH:29]=3)=[CH:34][CH:35]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)c1ccc(I)cc1
Reactant: Brc1ccc2c(c1)[nH]c1cc(Br)ccc12
Agent: Cl[Cu]
Agent: N#N
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(-n2c3cc(Br)ccc3c3ccc(Br)cc32)cc1
Temperature: 130 °C

Procedure:
A degassed solution of 489.5 mg (0.156%) of copper(I) chloride and 906 mg (1%) mmol) of 1,10-phenanthroline in 100 ml of toluene were saturated with N2 for 1 hour and heated to 130° C. The solution was subsequently admixed with 16.2 g (50 mmol) of 2,7-dibromocarbazole and 13.2 g (50 mmol) of 1-iodo-4-tert-butylbenzene and heated at 180° C. for 2 hours. After cooling, the mixture was admixed with 180 ml of water, the organic phase was separated off and the solvent was removed under reduced pressure. The product was recrystallized from n-hexane. Yield: 13 g (59%). Purity according to HPLC: 99.5%
Reaction SMILES: [C:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:16][CH:15]=2)=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH:25]=[CH2:26])[C:4]=1[CH3:27])#[N:2].O.[OH-].[Li+].CO>C1COCC1.O>[C:1]([C:3]1[C:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:18][CH:19]=2)=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH:25]=[CH2:26])[C:4]=1[CH3:27])#[N:2]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1c(C(=O)O)cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c1C
Temperature: 10 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution of methyl 4-cyano-2-ethenyl-3-methyl-5-[4-(1H-pyrazol-1-yl)benzyl]benzoate (0.70 g) in THF (5.00 mL)-water (5.00 mL) were added lithium hydroxide monohydrate (0.25 g) and methanol (1.00 mL), and the mixture was stirred at 10° C. for 16 hr. The reaction mixture was diluted with water, and the mixture was extracted with tert-butyl methyl ether. The aqueous layer was acidified with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.60 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CI.[CH3:25]COC(C)=O.O>CN(C=O)C.CC([O-])(C)C.[K+]>[NH2:1][C:2]1[C:3]([C:21]#[N:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:25])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (58 mg) was dissolved in DMF (1 ml). To the solution were added 1M MeI solution in DMF (0.22 ml) and 0.1M t-BuOK solution in DMF (2.2 ml). The mixture was stirred at 20-30° C. for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only-EtOAc:MeOH=93:7, v/v) to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile, which was crystallized from EtOAc (18 mg).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:26]=[CH:25][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:25][CH:26]=1
Reactant: N#Cc1ccc(COc2ccc([C@@H]3C[C@H]3N)cc2)cc1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Reaction time: 22 h
Yield: 43.5 %

Procedure:
A solution of methyl bromoacetate (0.08 mL, 0.91 mmol) in CH3CN (6 mL) was added, over a period of 15 min, to a solution of 4-({4-[(trans)-2-aminocyclopropyl]phenoxy}methyl)benzonitrile (0.22 g, 0.82 mmol) and DIPEA (0.28 mL, 1.64 mmol) in CH3CN (8 mL) at −10° C. The reaction was allowed to reach room temperature and stirred for 22 h. After removal of the solvent, the crude residue was purified by column chromatography on silica gel (2-5% MeOH/CH2Cl2) affording 0.12 g of methyl[((trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropyl)amino]acetate [Rf=0.5 (5% MeOH/CH2Cl2), pale yellow oil, 44% yield].
Reaction SMILES: [CH2:1]=O.[ClH:3].[CH3:4][NH:5][CH3:6].[Br:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[C:16]1[CH2:15][CH2:14][CH2:13][C:12](=[O:22])[C:11]2=1.O>C(O)(=O)C>[ClH:3].[Br:7][C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[C:16]1[CH2:15][CH2:14][CH:13]([CH2:4][N:5]([CH3:1])[CH3:6])[C:12](=[O:22])[C:11]2=1
Reactant: C=O
Reactant: Cn1c2c(c3cc(Br)ccc31)C(=O)CCC2
Reactant: CNC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CC1CCc2c(c3cc(Br)ccc3n2C)C1=O
Temperature: 25 °C
Yield: 67.3 %

Procedure:
Paraformaldehyde (1.5 g) and dimethylamine hydrochloride (3.75 g) were added to a solution of the product of Stage (iii) (10 g) in acetic acid (70 ml) and then heated to reflux for 8 h. On cooling to ambient temperature the reaction mixture was poured into water (400 ml). The oil which separated out was triturated with ether (500 ml) to give a solid (9 g) which was partitioned between ethyl acetate (2×30 ml) and saturated aqueous sodium carbonate (100 ml). The organic phase was evaporated and the residue purified by flash chromatography (G) to give the pure free base as a solid (0.40 g). A sample (0.4 g) was dissolved in ethanol (10 ml), filtered, and ethereal HCl (6 ml) was added. On addition of dry ether (20 ml), the title compound crystallized as a solid (0.38 g) m.p. 219°-220°.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([Br:34])[N:26]=2)=[O:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>O1CCOCC1>[Br:34][C:27]1[N:26]=[C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:14]3[NH:13][C:2](=[O:4])[O:17][C:16](=[O:18])[C:15]=3[CH:19]=2)=[O:24])[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O
Solvent: C1COCCO1
Product: O=C(c1ccc2[nH]c(=O)oc(=O)c2c1)c1nc(Br)c2ccccn12
Yield: 97.9 %

Procedure:
1.30 g (4.37 mmol) of triphosgene dissolved in 10 ml of dioxane are added, under an inert atmosphere at ambient temperature, to 1.05 g (2.91 mmol) of 2-amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid. The reaction medium is refluxed for 4 hours, and then concentrated under reduced pressure. 100 ml of water are added to the residue. The precipitate obtained is filtered off under reduced pressure at 40° C. for 18 hours. 1.1 g of a yellow solid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:25])([CH2:23]O)[CH2:21][OH:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:19][C:20]([CH3:25])([CH3:23])[CH2:21][OH:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CO)CO
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)CO
Reaction time: 23 h
Yield: 88.6 %

Procedure:
A mixture of N-benzyloxycarbonyl-L-valine (2.50 g, 10.0 mmol), 2,2-dimethyl-1,3-propanediol (5.30 g, 50.9 mmol), dicyclohexylcarbodiimide (2.60 g, 12.6 mmol), and 4-dimethylaminopyridine (125 mg, 1.0 mmol) in 100 mL dry CH2Cl2 was stirred for 23 h. The reaction mixture was filtered and washed successively with 50 mL each of water, saturated aqueous NH4Cl, saturated aqueous NaHCO3, and water. The organic phase was dried over anhydrous Na2SO4 and concentrated. The title compound (2.99 g, 87%) was isolated by flash column chromatography (silica, 2/1 petroleum ether-ethyl acetate) as a white waxy solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)([CH2:6][CH3:7])[CH2:4][OH:5].[CH2:26](Br)[C:27]#[CH:28]>>[CH2:28]([O:5][CH2:4][C:3]([O:2][CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)[CH2:6][CH3:7])[C:27]#[CH:26]
Reactant: C#CCBr
Reactant: CCC(CO)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Product: C#CCOCC(CC)(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 92 %

Procedure:
Using the procedure described in Example 8, 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]butan-1-ol (Example 6) with reacted with prop-2-ynyl bromide to give 2-methoxy-2-[3-(naphth-2-ylmethoxy)phenyl]but-1-yl prop-2-ynyl ether in 92% yield, m.p. 54° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:13]1[CH:22]=[C:21](Cl)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].ClC1C=C(Cl)C2C(=CC=C(Cl)C=2)N=1.C(N)CN>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH:22]=1
Reactant: Clc1cc(Cl)c2ccccc2n1
Reactant: CN(C)CCN
Reactant: c1ccc2c(c1)CCCNC2
Agent: Clc1ccc2nc(Cl)cc(Cl)c2c1
Solvent: NCCN
Product: CN(C)CCNc1cc(N2CCCc3ccccc3C2)nc2ccccc12

Procedure:
The title compound was prepared in analogy to Example 118-1 in Scheme 59 by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available), 2,4-dichloroquinoline (commercial available) and N,N-dimethyl-ethane-1,2-diamine (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine, 2,4,6-trichloroquinoline and ethane-1,2-diamine respectively. MS obsd. (ESi+) [(M+H)+] 361. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90 (d, J=3.6 Hz, 1 H), 7.56-7.46 (m, 3 H), 7.15-7.11 (m, 4 H), 5.89 (s, 1 H), 4.87 (s, 2 H), 4.14 (s, 2 H), 3.53 (s, 2 H), 3.05 (s, 2 H), 2.91 (s, 2 H), 2.53 (s, 6 H), 1.80 (s, 2 H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][C:2]2=O.[O:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:15][NH2:16].[S-:17][C:18]#[N:19].[K+].II>C(#N)C>[O:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:15][N:16]1[C:2]2[CH:1]3[O:8][CH:5]([CH2:4][C:3]=2[S:17][C:18]1=[NH:19])[CH2:6][CH2:7]3
Reactant: NC[C@H]1CCCO1
Reactant: O=C1CCC2CCC1O2
Reactant: N#C[S-]
Agent: II
Agent: [K+]
Solvent: CC#N
Product: N=c1sc2c(n1C[C@H]1CCCO1)C1CCC(C2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.5 %

Procedure:
A mixture of 8-oxabicyclo[3.2.1]octan-2-one (obtained as described in Vogel et al. Tetrahedron 1993, 49 (8), 1649-1664) (0.53 g, 4.2 mmol), (R)-(tetrahydrofuran-2-yl)methanamine (0.43 mL, 4.2 mmol) and 1 g of 4 Å molecular sieves (8-12 mesh beads) in acetonitrile (4 mL) was stirred at ambient temperature for 16 h. The material was filtered through Celite® with acetonitrile (additional 10 mL) then the filtrate treated with potassium thiocyanate (0.54 g, 5.6 mmol) was added and the mixture was warmed to 50° C. Iodine (2.1 g, 8.4 mmol) was added and the mixture stirred at 50° C. for 72 h. The mixture was cooled to ambient temperature and was concentrated under reduced pressure. The crude material was diluted with 20 mL CH2Cl2 and was stirred with sodium metabisulfite (20 mL of 20% aqueous solution) for 15 min. The layers were separated and the aqueous layer was extracted 3×10 mL CH2Cl2. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude material (1.0 g, 3.8 mmol, 89% yield) which was carried on without further purification. MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[S:22][C:23]([CH:26]=O)=[CH:24][CH:25]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][NH2:32].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[S:22][C:23]([CH2:26][NH:32][CH3:31])=[CH:24][CH:25]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)s4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC)s4)cc23)CC1
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-2-thienyl)-1H-indole-7-carboxamide (35 mg, 0.078 mmol) in DMSO (1.0 mL) was added acetic acid (3 drops), 2 M methylamine in THF (0.24 mL, 0.471 mmol), and reacted for 3 h. Sodium triacetoxyborohydride (100 mg, 0.471 mmol) was then added and reaction was stirred overnight. All solvent was removed in vacuo and purified by Gilson Preparatory HPLC. The impure desired fraction was concentrated under reduced pressure and loaded onto a 500 mg SCX SPE cartridge primed with 10 mL of methanol. The cartridge was then sequentially eluted with 2M NH3 in MeOH (10 mL×2). The NH3 in MeOH fractions were concentrated to give 7.3 mg of the title compound (20%).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]([O:15][CH3:16])(=[O:14])/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11]>C1(C)C=CC=CC=1>[CH3:3][C:2]1[CH2:1][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[C@H:8]([C:7]([O:15][CH3:16])=[O:14])[CH2:5][C:4]=1[CH3:6]
Reactant: C=C(C)C(=C)C
Reactant: COC(=O)/C=C/C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)OC

Procedure:
2,3-dimethylbutadiene (9.84 g, 0.12 mol) and dimethyl fumarate (14.4 g, 0.1 mol) were stirred together in toluene (40 ml) at 50° C. for 24 hr. The solvent was removed in vacuo and the solid residue recrystallised from diethyl ether, to give the title compound in 85%, yield. N.m.r: δH (90 MHz, CD3OD) 3.71 (s,6H), 2.55 (m,2H), 2.10 (m,4H), 1.74 ppm (s,6H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=[O:6].[H-].[Na+].C(OC(=O)C)C>CN(C=O)C.C1COCC1>[C:10]1([CH3:14])[CH:11]=[CH:12][CH:13]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:9]=1
Reactant: Cc1cccc(NC(=O)NCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCNC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
1-(2-Chloro-ethyl)-3-m-tolyl-urea (I-131a: 4 g, 18.86 mmol) in dry DMF (70 mL) was added to a stirred mixture of sodium hydride (1.358 g, 28.30 mmol) in THF (70 mL) at 0° C. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with MeOH at 0° C., concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford 2.7 g (81.34% yield) of 1-m-tolyl-imidazolidin-2-one.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1.C(O[CH2:14][CH2:15][C:16]#[N:17])C>C(O)C>[NH2:17][C:16]1[CH2:15][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][N:7]=2)[N:10]=1
Reactant: CCOCCC#N
Reactant: NNc1ccc(Cl)cn1
Agent: [Na]
Solvent: CCO
Product: NC1=NN(c2ccc(Cl)cn2)CC1

Procedure:
A 0.08 g. amount of sodium metal is dissolved in 10 ml. of absolute ethanol, then 2.5 g. of 5-chloro-2-hydrazinopyridine is added, followed by 1.70 g. of beta-ethoxypropionitrile. The procedure of Example 1 is continued to give 1.40 g. of the product of the Example as yellow crystals, m.p. 203°-204.5° C.